Tumor metastasis is a complex, multi-step process in which cancer cells detach from the original tumor mass and establish metastatic foci at organ-specific sites (Fidler, I. J., Surg Oncol Clin N Am 10: 257-269, vii-viiii. (2001)). The location of the metastatic site depends on the particular type of cancer and stage of disease. For example, breast cancer typically spreads first to the lungs and liver (Kamby, C. et al., Cancer 59: 1524-1529 (1987); Rutgers, E. J. et al., Br J Surg 76: 187-190 (1989); Tomin, R. and Donegan, W. L., J Clin Oncol 5: 62-67 (1987)). Later in the disease, breast cancer spreads to the central nervous system and bone (Amer, M. H., J Surg Oncol 19: 101-105 (1982); Boogerd, W., Radiother Oncol 40, 5-22(1996)). The metastatic phase of the disease is devastating, given that conventional treatments are usually ineffective and patients typically survive only a few years after diagnosis (Harris, J. et al., Cancer of the breast. In Cancer, principles and practice of oncology (Philadelphia, Lippincott Co.), pp. 1602-1616 (1982)).
Several factors affect the location and growth of metastases. Depending on the blood-flow pattern from the primary tumor, certain tumor cells are carried preferentially to particular organs (Weiss, L., Clin Exp Metastasis 10: 191-199 (1992)). While in circulation, some tumor cells selectively recognize particular endothelial cell surface molecules that mediate cell adhesion to specific organs (Abdel-Ghany, M. et al., J Biol Chem 276: 25438-25446 (2001); Cheng, H. C. et al., J Biol Chem 273: 24207-24215 (1998); Johnson, R. C. et al., J Cell Biol 121: 1423-1432 (1993)). The arrest of tumor cells at the metastatic site, through mechanical trapping in small capillaries or through adhesive interactions with the endothelium, is a necessary step for tumors to become established at a secondary site (Chambers, A. F. et al., Nat Rev Cancer 2: 563-572 (2002); Orr, F. W. and Wang, H. H., Surg Oncol Clin N Am 10: 357-381, ix-x (2001)). Once the tumor cells have seeded the target organ, the local microenvironment influences whether or not a particular cancer cell will proliferate (Fidler, I. J., Surg Oncol Clin N Am 10: 257-269, vii-viiii (2001); Radinsky, R., Cancer Metastasis Rev 14: 323-338 (1995)). Unfortunately, many of the factors that contribute to organ-specific metastasis have yet to be elucidated.
Of the many possible factors, one such possible factor may be the protein or proteins that allow homing of a protein or a cell to a particular tissue by binding to a molecule in the tissue. Some lung-specific homing peptides have been isolated by in vivo phage display (Rajotte, D. and Ruoslahti, E., J Biol Chem 274: 11593-11598 (1999)) and antibodies that specifically bind to lung vasculature have been prepared (McIntosh, D. P., et al., Proc Natl Acad Sci USA 99: 1996-2001 (2002)). Tissue-specific expression of vascular markers is not limited to lung vasculature; recent data suggest that each tissue puts a specific signature on its vasculature (Ruoslahti, E., Nat Rev Cancer 2: 83-90 (2002)). Thus, binding of tumor cells to tissue-specific vascular markers may play a role in selective tumor metastasis to other tissues as well.
There are examples of adhesive interactions that are required in order for lung metastases to form. Dipeptidyl dipeptidase IV on lung endothelial cells was found to be an adhesion receptor for fibronectin on metastasizing breast and prostate carcinoma cells in a mouse model (Cheng, H. C. et al., J Biol Chem 273: 24207-24215 (1998); Johnson, R. C., et al., J Cell Biol 121: 1423-1432 (1993)). In another mouse model, Ca2+-sensitive chloride channel, hCLCA2, on lung endothelial cells was reported to be a ligand for β4 integrins on metastasizing breast cancer cells (Abdel-Ghany, M., et al., J Biol Chem 276: 25438-25446 (2001); Elble, R. C., et al., J Biol Chem 272: 27853-27861 (1997)). Most recently, the secreted chemokine, CXCL12, which is highly expressed in the lung, liver, and lymph nodes, was shown to bind to CXCR4 receptors on the surface of metastasizing breast cancer cells (Muller et al., 2001). Moreover, interfering with only one of these interactions was sufficient to inhibit metastasis (Abdel-Ghany, M., et al., J Biol Chem 276: 25438-25446 (2001); Cheng, H. C. et al., J Biol Chem 273: 24207-24215 (1998); Muller, A., et al., Nature 410: 50-56 (2001)). Although there is no evidence available on the significance of these interactions in breast cancer, it seems that multiple interactions of cell adhesion molecules and growth factor receptors may be required for the attachment and growth of circulating tumor cells. Similar mechanisms based on unique vascular addresses may play a role in organ-specific metastasis to other organs.
Others have identified numerous genes, whose expression are increased in metastatic breast cancer. One such gene, described as GenBank™ entry AK000745 was up-regulated in metastatic breast cancers, along with many other genes (Van't Veer, et al., Nature 415: 530-536 (2002). However, the possibility of a causal role of this gene or its protein product (herein named metadherin) in breast cancer metastasis has not yet been established.